Utilization of tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinone as a cap moiety in design of novel histone deacetylase inhibitors

被引：47

作者：

Mohamed, Mamdouh F. A. ^{[1
]}

Youssif, Bahaa G. M. ^{[2
,3
]}

Shaykoon, Montaser Sh A. ^{[4
]}

Abdelrahman, Mostafa H. ^{[5
]}

Elsadek, Bakheet E. M. ^{[6
]}

Aboraia, Ahmed S. ^{[7
]}

Abuo-Rahma, Gamal El-Din A. ^{[8
]}

机构：

[1] Sohag Univ, Fac Pharm, Dept Pharmaceut Chem, Sohag 82524, Egypt

[2] Assiut Univ, Fac Pharm, Dept Pharmaceut Organ Chem, Assiut 71526, Egypt

[3] Jouf Univ, Coll Pharm, Dept Pharmaceut Chem, Sakaka 2014, Aljouf, Saudi Arabia

[4] Al Ashar Univ, Fac Pharm, Dept Pharmaceut Chem, Assiut 71524, Egypt

[5] Al Ashar Univ, Fac Pharm, Dept Pharmaceut Organ Chem, Assiut 71524, Egypt

[6] Al Ashar Univ, Fac Pharm, Dept Biochem, Assiut 71524, Egypt

[7] Assiut Univ, Fac Pharm, Dept Med Chem, Assiut 71526, Egypt

[8] Menia Univ, Fac Pharm, Dept Med Chem, Al Minya 61519, Egypt

来源：

BIOORGANIC CHEMISTRY | 2019年 / 91卷

关键词：

Tetrahydrobenzo[4,5]Thieno[2,3-d]pyrimidinone; Histone deacetylase inhibitors; Molecular docking; Anti-proliferative; Apoptotic assay; BIOLOGICAL EVALUATION; ACID-DERIVATIVES; ANTICANCER; THIENOPYRIMIDINE; CANCER; SCAFFOLD; GROWTH; AGENTS;

D O I：

10.1016/j.bioorg.2019.103127

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of novel 5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one derivatives bearing a hydroxamic acid, 2-aminoanilide and hydrazide moieties as zinc-binding group (ZBG) were designed, synthesized and evaluated for the HDAC inhibition activity and antiproliferative activity. Most of the tested compounds displayed strong to moderate HDAC inhibitory activity. Some of these compounds showed potent anti-proliferative activity against human HepG2, MCF-7 and HCT-116 cell lines. In particular, compounds IVa, IVb, IXa and IXb exhibited significant anti-proliferative activity against the three cell lines tested compared to SAHA as a reference. Compound IVb is equipotent inhibitor for HDAC1 and HDAC2 as SAHA. It is evident that the presence of free hydroxamic acid group is essential for Zn binding affinity with maximal activity with a linker of aliphatic 6 carbons. Docking study results revealed that compound IVb could occupy the HDAC2 binding site and had the potential to exhibit antitumor activity through HDAC inhibition, which merits further investigation.

引用

页数：13